: While head and neck squamous cell carcinoma (HNSCC) related to environmental carcinogens (tobacco, alcohol) has declined in the US, the incidence of oropharyngeal cancer (OPC? cancer of the tonsil and base of tongue) related to the human papilloma virus (HPV) is rising sharply. Conventional treatment for HPV-related oropharyngeal cancer (HPVOC)is highly effective, but can be associated with significant short- and long-term toxicities, which for some patients result in lifelong speech and swallowing dysfunction. However, due to the lack of prospective trials in this population, the high cure rates and unique survivorship issues of HPVOPC patients are not reflected in current treatment guidelines, which make no distinction between HPV-positive and HPV-negative OPC. Thus, there is an urgent unmet medical need for new HPVOPC treatment strategies with the potential to reduce or eliminate toxic chemotherapy and/or radiation while preserving outstanding treatment results in this population. In HPVOPC HPV-specific immune responses are often detected but ineffective. We propose to undertake a phase II clinical trial to test the hypothesis that stimulating anti-HPV immunity with ADXS11-001, a novel immunotherapy, will elicit robust anti-tumor immune responses in HPVOPC patients. Endpoints will include parallel assessments of pre- and post-treatment HPV-specific immune responses in the peripheral blood, multi-parameter immunophenotyping by flow cytometry, multiplex cytokine analysis, and immunohistochemistry to profile the pattern of immune infiltration in the tumor microenvironment before and after treatment. Direct evidence of immune stimulation by ADXS11-001 in HPVOPC patients will support the concept of immunomodulation as a novel therapeutic approach to patients with HPVOPC